GABA-A receptors are thought to mediate several effects of alcohol. GABA-A receptors are pentameric ligand-gated ion channels. Currently, seven different receptor subunit classes have been discovered (alpha 1-6, beta 1-3, gamma 1-3, rho 1-3, delta, epsilon, theta), and the presence of certain subunits can have profound effects on receptor pharmacology. Indeed, data has shown that whereas alphal-receptor subunits mediate the sedative, amnestic, and some anticonvulsant effects, alpha2 receptor subunits mediate the anxiolytic effects ofbenzodiazepines. Moreover, pharmacological data suggests that alpha5 subunits mediate alcohol's reinforcing properties. In the current proposal, we aim to investigate the alcohol sensitivity of GABA-A alpha2- and alpha5-receptor subunit null mutant mice. We predict that these null mutations will result in subunit specific changes in alcohol sensitivity. We hypothesize that deletion of the alpha2 gene will result in reduced sensitivity to alcohol's anxiolytic effects, whereas null mutation of the alpha5 gene will result in reduced sensitivity to alcohol's reinforcing properties. It is our hope that these data will aid in research aimed at identifying potential pharmacological treatment strategies for alcoholism.